The present invention relates to radiolabelled imidazo[1,2-a]pyridines and related compounds which bind to peripheral benzodiazepine receptors and are useful for imaging such receptors and providing therapeutic treatment including radiotherapy.
The peripheral benzodiazepine receptors, which are also commonly referred to as the mitochondrial benzodiazepine receptors or xcfx89-3-receptors, are distinct from the central benzodiazepine receptors in their pharmacology, subcellular location and structural requirements. Peripheral benzodiazepine receptors are predominantly found in the peripheral organs such as kidney, heart, adrenal cortex, testis, ovaries, plasma (platelets) as well as in the glial cells and olfactory bulbs in the brain. It has also been reported that peripheral benzodiazepine receptor density is higher in tumours, such as glioma, ovarian and colon carcinoma, than in corresponding normal tissue. Recently high concentration of peripheral benzodiazepine receptors has been reported in Dunning rat prostate tumours compared to the normal ventral or dorsolateral prostate.
The peripheral benzodiazepine receptors appear to be associated (but not exclusively) with the outer mitochondrial membrane in many tissues where they are modulated by hormones and drugs and reflect the effects of emotional stress, and hypertension. Peripheral benzodiazepine receptors in the brain have been investigated for use as markers of neurodegeneration including Huntington""s disease, Alzheimer""s disease, anxiety, stress, emotional disturbances, cognitive impairment, stroke, and cerebral ischemia. Several classes of ligands have been shown to exhibit high affinity binding to the peripheral benzodiazepine receptor, the most widely investigated being the benzodiazepine Ro 5-4864 (7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one) and the isoquinoline PK-11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide). Labelled with 11C, 18F and 123I, these ligands have been used to map peripheral benzodiazepine receptors in the human heart and brain. Enhanced uptake of [3H]PK-11195 has been reported in a variety of tumour cells including breast, ovarian, prostate, adrenal, brain and colon. Radiolabelling with suitable levels of radioactive iodine may be used firstly to diagnose these tumours (using radiolabels such as 123I or 131I) and subsequently to treat them with therapeutic doses (for instance using 123I, 125I or 131I). Furthermore, recent work has also revealed the existence of several binding domains which differ in affinity for isoquinoline and benzodiazepine ligands at different organs and species.
Various 2-aryl substituted imidazo[1,2-a]pyridines having anxiolytic, hypnotic, anticonvulsant, analgesic and other properties have been reported (Almirante L. et al., J. Med. Chem. 12 122-126 (1969); Langer S. Z. et al., Pharmacol. Biochem, Behav. 29 763-766 (1988); Langer S. Z. et al., Pharmacopsychiatry 23 103-107 (1990); Bourguignon, J-J., xe2x80x9cEndogenous and Synthetic Ligands of Mitochondrial Benzodiazepine Receptors: Structure Affinity Relationshipsxe2x80x9d in Giesen-Grouse. E. ed. Peripheral Benzodiazapine Receptors, Academic Press, London (1993)). For example 123I labelled 6-methyl-2-(4xe2x80x2-iodophenyl)imidazo[1,2-a]pyridine-3-(N,N-dimethyl)acetamide has been reported as a potential tracer for the study of the peripheral benzodiazepine receptor using SPECT (Katsifis A. et al., J. Lab. Comp. Radiopharm. 40 620-622 (1997)).
However, the compounds which have been described previously typically exhibit strong binding to the central benzodiazepine receptors, even if they also bind to peripheral benzodiazepine receptors (see for example Anzini M. et al., J. Med. Chem. 39 4275-4284 (1996) and Trapani G. et al. J. Med. Chem. 40 3109-3118 (1997)). Hence, the prior art compounds are not sufficiently selective for peripheral benzodiazepine receptors to be useful for diagnosis or therapy of conditions associated with a high density of those receptors. Thus there is a need for substances that bind strongly to peripheral benzodiazepine receptors but do not bind strongly to central benzodiazepine receptors.
Surprisingly, the present inventors have discovered that certain 2-(iodophenyl)-imidazo[1.2-a]pyridines having an electronegative substituent especially halogen, in the pyridine nucleus exhibit strong binding to peripheral benzodiazepine receptors and much weaker binding to central benzodiazepine receptors. Hence the compounds of the present invention have superior properties, as far as the PET and SPECT imaging of peripheral benzodiazepine receptors is concerned, compared to related substances which have been reported previously.
The compounds of the present invention, appropriately labelled, are clinically useful in SPECT and PET scanning, for example to detect those cancers which express high density of the peripheral benzodiazepine receptors and/or to detect, or non-invasively diagnose, neurodegenerative disorders. The compounds of the present invention are also useful for the treatment of disorders characterised by an abnormal density of peripheral benzodiazepine receptors, such as neurodegenerative disorders and tumours.
In a first embodiment, the invention provides a compound of formula (I) 
wherein
Y is selected from F, Cl, Br, I, OH, SH, NH2, CN, and COOH;
Z is selected from N(R3)C(O)R4 and C(O)NR3R4;
R1 and R2 are independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C6-C12)aryl, (C6-C12)aryloxy, (C6-C12)aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, heterocyclic, (C2-C6)alkanoyl and (C2-C7)acyl, each of which may be unsubstituted OF substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C1-C4)alkoxy, SH, NH2, (C1-C4)alkylamino, di((C1-C4)alkyl)amino, carboxy, (C1-C4)alkoxycarbonyl. (C2-C4)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH;
R3 and R4 are each independently hydrogen or a group selected from (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C6-C12)aryl, (C6-C12)aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4)alkyl, heterocyclic, (C1-C4)alkoxycarbonyl and (C2-C5)acyl, each of which may be unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C1-C4)alkoxy, SH, NH2, (C1-C4)alkylamino, di((C1-C4)alkyl)amino, carboxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH,
or R3 and R4 together are (C2-C7) alkylidene which may be optionally substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C1-C4)alkoxy, SH, NH2, (C1-C4)alkylamino, di((C1-C4)alkyl)amino, carboxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH;
m and n are independently 0, 1 or 2; and
p is 1.
In a second embodiment, the invention provides a compound of the first embodiment which is radiolabelled.
The invention further provides a pharmaceutical composition including a compound of the first or second embodiment together with at least one pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
In a third embodiment, the invention further provides a method for diagnosis of a disorder in a mammal characterised by an abnormal density of peripheral benzodiazepine receptors, the method including the steps of:
administering to the mammal an amount of a radiolabelled compound of the second embodiment sufficient to allow a detectable image of the location of the radiolabel in the body of the mammal to be recorded;
recording a image of the distribution of the radiolabel in at least part of the body of the mammal; and
diagnosing the presence or absence of the disorder from the image.
In a fourth embodiment, the invention provides a method for the treatment of a disorder characterised by an abnormal density of peripheral benzodiazepine receptors in a mammal in need of said treatment, the method including administering to the mammal an effective amount of a compound of the first embodiment, or a pharmaceutical composition thereof.
In a fifth embodiment, the invention provides a method for the radiotherapy of a disorder characterised by an abnormal density of peripheral benzodiazepine receptors in a mammal in need of said radiotherapy, the method including administering to the mammal an effective amount of a compound of the second embodiment, or a pharmaceutical composition thereof.
In a sixth embodiment, the invention provides the use of a compound of the second embodiment for the manufacture of a diagnostic composition for the diagnosis of a disorder in a mammal characterised by an abnormal density of peripheral benzodiazepine receptors.
In a seventh embodiment, the invention provides the use of a compound of the first embodiment for the manufacture of a medicament for the treatment of a disorder characterised by an abnormal density of peripheral benzodiazepine receptors in a mammal in need of said treatment.
In an eighth embodiment, the invention provides the use of a compound of the second embodiment for the manufacture of a medicament for the radiotherapy of a disorder characterised by an abnormal density of peripheral benzodiazepine receptors in a mammal in need of said radiotherapy.
In a ninth embodiment, the invention provides a compound of the second embodiment when used in a method of the third embodiment.
In a tenth embodiment, the invention provides a compound of the first embodiment when used in a method of the fourth embodiment.
In an eleventh embodiment, the invention provides a compound of the second embodiment when used in a method of the fifth embodiment.
As used herein, the term xe2x80x9calkylxe2x80x9d includes within its meaning straight and branched chain alkyl groups. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl and 1,1,2-trimethylpropyl.
A used herein, the term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups, or alkyl substituted cyclic alkyl groups. Examples of such groups include cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl and the like.
As used herein, the term xe2x80x9calkoxyxe2x80x9d refers to a group of the formula alkyl-O-, wherein the alkyl group is as defined above.
As used herein, the term xe2x80x9calkenylxe2x80x9d includes within its meaning ethylenically mono- or di-unsaturated alkyl or cycloalkyl groups as previously defined. Examples of such alkenyl groups are vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl , 1-methyl-cyclopentyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl.
As used herein, the term xe2x80x9calkynylxe2x80x9d includes within its meaning acetylenically unsaturated alkyl groups as previously defined. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-1-butynyl, n-hexynyl and methyl-pentynyl.
As used herein, the term xe2x80x9calkylidenexe2x80x9d refers to optionally unsaturated divalent alkyl radicals. Examples of such radicals are xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94CH2CH2CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and xe2x80x94(CH2)rxe2x80x94 where r is 5-7. The term also refers to optionally unsaturated divalent alkyl radicals in which one or more of the bonds of the radical from part of a cyclic system.
As used herein, the term xe2x80x9carylxe2x80x9d refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons. Examples of such groups are phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl and azulenyl. Any available position of the aromatic residue can be used for attachment to the remainder of the molecule of formula (I).
As used herein, the term xe2x80x9caryloxyxe2x80x9d refers to a group of the formula aryl-O-, wherein the aryl group is as defined above.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to single, polynuclear, conjugated and fused residues of aromatic heterocyclic ring systems. Examples of such groups are pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, indolyl, pyridazinyl, pyrazolyl, pyralzinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Any available position of the heteroaromatic residue can be used for attachment to the remainder of the molecule of formula (I).
As used herein, the term xe2x80x9cheterocyclicxe2x80x9d refers to any 3- to 12-membered monocyclic, bicyclic or polycyclic ring containing, for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered rings, from one to five heteroatoms; for 12-membered rings, from one to six heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur. The term xe2x80x9cheterocyclicxe2x80x9d includes any group in which a heterocyclic ring is fused to a benzene ring. Examples of heterocyclics are pyrryl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, piperidinyl, pyridinyl, furyl, thiophenyl, tetradhyrofuryl, imidazolyl, oxazolyl, thiazolyl, pyrenyl, oxazolidinyl, isooxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, furfuryl, thienyl, benzothienyl, benoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, azanorbornyl, isoquinuclidinyl and the like. Nitrogen-containing heterocyclics may be substituted at nitrogen with an oxygen atom. Sulfur-containing heterocyclics may be substituted at sulfur with one or two oxygen atoms. Configurations of heteroatoms which result in unstable heterocyclics are not included within the scope of the definition of xe2x80x9cheterocyclicxe2x80x9d.
As used herein, the term xe2x80x9calkanoylxe2x80x9d refers to groups of the formula alkyl-C(O)Oxe2x80x94, wherein the alkyl group is as defined above.
As used herein, the term xe2x80x9cacylxe2x80x9d refers to any group of formula QC(O)xe2x80x94, wherein Q is amino, alkylamino, dialkylamino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocyclic, each of which may be unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C1-C4)alkoxy, SH, NH2, (C1-C4)alkylamino, di((C1-C4)-alkyl)amino, carboxy, (C1-C4)alkoxycarbonyl, (C2-C4)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH.
A compound of the second embodiment may be radiolabelled by any convenient radionuclide. Typically, the radionuclide is an emitter of particles whose energy is suitable for imaging of the emission, or which are suitable in radiation therapy. For example, the radionuclide may be 11C, 18F, 76Br or 123I. Usually, the radionuclide is a radionuclide of iodine, such as 123I, 124I, 125I or 131I. For radiotherapy, the radionuclide is typically 123I, 125I or 131I.
Compounds in accordance with the invention may be synthesised by methods which are generally known in the art. One possible synthesis of imidazo[1,2-a]pyridines in accordance with the present invention is illustrated in Scheme 1.
As shown in Scheme 1, reaction of an xcex1-bromoacctophenone (IIb) with a 2-amino-pyridine (IIa) in ethanol or similar solvent yields an imidazo[1,2-a]pyridine (III). An aminomethyl moiety may be introduced at the 3-position by treatment of the imidazo-[1,2-a]pyridine with, for example, dimethylamine and formaldehyde in aqueous medium. The resulting aminomethyl substituent may be demethylated by known methods and acylated to yield compounds of the present invention, or it may be elaborated to an amidomethyl substituent as shown in Scheme 1. Methylation of the aminomethyl group, followed by treatment with potassium cyanide, yields the 3-cyanomethyl imidazo[1,2-a]pyridine (VI), which may be converted to a range of amidomethyl analogs (VIII) by standard methods.
Scheme 2 illustrates a method for preparing N-alkynyl and N-(iodoalkenyl) examples (IX) and (X) respectively, of compound (VIII) from carboxymethyl derivative (VII). 
When the radionuclide in a compound of the second embodiment of the invention is a nuclide of iodine, it may conveniently be introduced as the iodo substituent on the 2-phenyl substituent of the imidazo[1,2-a]pyridine or the substituent Y in the compound of formula (I). A scheme for introducing 123I (or other isotope of iodine, *I) is illustrated in Scheme 3.
As shown in Scheme 3 starting from a 2-(bromophenyl) or 2-(iodophenyl) imidazo[1,2-a]pyridine (VII) (a 2-(bromophenyl) compound is shown) the corresponding tributyl stannane is prepared by treating the starting material with bistributyltin and palladium tetrakistriphenylphosphine in refluxing toluene, dioxane, or toluene/DMF for 6-24 hours. The resultant stannanes can be purified by column chromatography and/or by recrystallisation from ethyl acetate/hexane. The radiolabelled iodine analogs are prepared by electrophilic iododestannylation of the tributyltin derivative with Na*1 in the presence of peracetic acid, chloramine-T, iodogen or other oxidising agent in an appropriate solvent such as ethanol/methanol or acetic acid at room temperature. 
Starting materials for synthesis of compounds according to the invention are either commercially available, or are known compounds, or are compounds whose synthesis presents no difficulty to a person of ordinary skill in the relevant art. In some cases, where the presence of a functional group an a substituent of a molecule may interfere with the desired synthetic step such as any of those shown in Schemes 1 to 3, it will be necessary to appropriately protect the functional group. Suitable protecting groups are generally known in the art, and are described, for example, in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, John Wiley and Sons Inc. New York (1991), the disclosure of which is incorporated herein by reference.
A pharmaceutical composition in accordance with the invention may be administered orally, topically, parenterally, e.g. by injection and by intra-arterial infusion, rectally or by inhalation spray.
For oral administration, the pharmaceutical composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, granules, suspensions, emulsions, syrups and tinctures. Slow-release, or delayed-release, forms may also be prepared for example in the form of coated particles, multi-layer tablets or microgranules.
Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharinc. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoale, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
The emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.
For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion. The pharmaceutical composition may contain pharmaceutically acceptable binders, diluents, disintegrating agents, preservatives, lubricants, dispersing agents, suspending agents and/or emulsifying agents as exemplified above.
For parenteral administration, the compound of formula (I) or its salt may be prepared in sterile aqueous or oleaginous solution or suspension. Suitable non-toxic parenterally acceptable diluents or solvents include water, Ringer""s solution, isotonic salt solution, 1,3-butanediol, ethanol, propylene glycol or polyethylene glycols in mixtures with water. Aqueous solutions or suspensions may further comprise one or more buffering agents. Suitable buffering agents include sodium acetate, sodium citrate, sodium borate or sodium tartrate, for example.
For rectal administration, the compound of formula (I) is suitably administered in the form of an enema or suppository. A suitable suppository may be prepared by mixing the active substance with a non-irritating excipient which is solid at ordinary temperatures but which will melt in the rectum. Suitable such materials are cocoa butter and polyethylene glycols. Suitable enemas may comprise agents as exemplified above with reference to forms for topical administration.
Suitably, an inhalation spray comprising a compound of formula (I) will be in the form of a solution, suspension or emulsion as exemplified above. The inhalation spray composition may further comprise an inhalable propellant of low toxicity. Suitable propellants included carbon dioxide or nitrous oxide.
Pharmaceutical compositions, diagnostic compositions and medicaments including comounds of the first or the second embodiment may be manufactured by methods which are generally known in the art. Typically such compositions or medicaments are prepared by grinding, crushing, blending, dispersing, dissolving, suspending, mixing, admixing, combining, emulsifying or homogenising a compound of the first or second embodiment with one or more suitable carriers, adjuvants, diluents or excipients. Combinations of two or more of the foregoing steps may also be employed.
The dosage form of the compound of formula (I) will include from 0.01% to 99% by weight of the active substance. Usually, dosage forms according to the invention will comprise from 0.1% to about 10% by weight of the active substance.
In a diagnostic method in accordance with the third embodiment of the invention, a dosage of typically from about 3 to about 25 mCi of a compound of the second embodiment is typically administered to a mammal, usually a human, in whom it is desired to diagnose the presence or absence of a disorder characterised by an abnormal density of peripheral benzodiazepine receptors. After a period of from 0.5 to 60 hours following administration of a compound of the second embodiment, more typically from 1 to 40 hours, an image of the distribution of radioactivity in the body, or part of the body, of the mammal is obtained. It will be appreciated that the lower doses are appropriate for administration to a child, and the higher dosages are more appropriate for administration for diagnosis of a tumour where imaging is to be carried out 24 hours or more after administration of the substance. The presence of a concentration of radioactivity at a site where an abnormal density of peripheral benzodiazepine receptors occurs in a mammal suffering from the disorder indicates a positive diagnosis.
A method in accordance with the fourth embodiment includes the administration to a mammal, typically a human, of a compound of the first embodiment. The administered dosage of the compound of formula (I) can vary and depends on several factors, such as the condition of the patient. Dosages will range from 0.01 mg to 200 mg per kg. Usually, the dose of the active substance will be from 0.01 mg to 10 mg per kg of body weight.
In a method in accordance with the fifth embodiment of the present invention involving the administration of a radiolabelled compound of the second embodiment, or a pharmaceutical or diagnostic composition thereof. the dosage administered is typically in the range of from 1-3 mCi per kg of body weight of the mammal, or from 10-300 mCi, more typically 50-300 mCi, per dose. The mammal is typically a human.
A therapeutic or radiotherapeutic dosage of a compound of the first or second embodiment of the invention will be determined by the attending physician in any gven circumstance, depending on factors such as the condition which is to be treated in the patient, and its severity.
Conditions for the treatment of which compounds in accordance with the invention are useful are conditions associated with abnormal density of peripheral benzodiazepine receptors such as neurodegenerative disorders, including Huntington""s disease, Alzheimer""s disease, anxiety, stress, emotional disturbances, cognitive impairment, stroke, and cerebral ischemia; certain tumours, such as glioma, and carcinoma of the ovary, colon, breast, prostate, brain and adrenals; neurotoxic injury, including that associated with anoxia or ischemia which may result from stroke or cardiac arrest; cognitive disorders, and in cognitive enhancement.
A compound in accordance with the invention may be administered in a single dose, or in two doses, or in multiple doses, depending on the disorder, the stage of the disorder, its response to the treatment, and any undesirable effects which may become apparent.
In one form of the present invention, the compound of formula (I) is a compound wherein:
Y is selected from F, Cl, Br, I, CN and OH;
Z is selected from N(R3)C(O)R4 and C(O)NR3R4;
R1 and R2 are independently selected from (C1-C3)alkyl, (C1-C3)alkoxy, (C2-C3)alkenyl, (C5-C6)cycloalkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzyl, pyridyl, furanyl, thienyl, piperidinyl, morpholinyl, tetrahydrofuranyl, dioxanyl, (C2-C4)alkanoyl and (C2-C4)acyl, each of which may be unsubstituted or substituted with from a substituent selected from the group consisting of halogen, OH, (C2-C4)alkoxy, NH2, (C1-C3)alkylamino, di((C1-C3)alkyl)amino, carboxy, (C1-C3)alkoxycarbonyl, (C2-C4)alkanoyl, oxo and amido;
R3 and R4 are each independently hydrogen or a group selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C5-C6)cycloalkyl, phenyl, naphthyl, benzyl and (C2-C4)acyl, each of which may be unsubstituted or substituted with a substituent selected from the group consisting of halogen, OH, (C1-C3)alkoxy, NH2, (C1-C3)alkylamino, di((C1-C3)alkyl)-amino, carboxy, (C1-C3)alkoxycarbonyl, (C2-C4)alkanoyl, oxo and amido,
or R3 and R4 together are (C2-C3)alkylidene which may be optionally substituted with from a substituent selected from the group consisting of halogen, OH, (C1-C3)alkoxy, NH2, (C1-C3)alkylamino, di((C1-C3)alkyl)amino, carboxy, (C1-C3)alkoxycarbonyl, (C2-C4)alkanoyl, oxo and amido;
m and n are independently 0 or 1; and
p is 1.
In yet another form of the present invention, the compound of formula (I) is a compound wherein n is 0.
In still another form of the present invention, the compound of formula (I) is a compound wherein p is 1, and n and m are each 0.
In even another form of the present invention, the compound of formula (I) is a compound herein p is 1, n and m are each 0, and Y is selected from F, Cl, Br, and I.
In a further form of the present invention, the compound of formula (I) is a compound wherein p is 1, n and m are each 0, and Y is selected from Cl and Br.
In a still further form of the present invention, the compound of formula (I) is a compound wherein p is 1, n and m are each 0, Y is selected from Cl and Br and Z is C(O)NR13R14, wherein R13 and R14 are independently selected from hydrogen, (C1-C4)alkyl and (C2-C4)alkenyl, each of which may be substituted with iodine.
In yet a further form of the invention, the compound of formula (I) is a 2-(4xe2x80x2-iodophenyl)-imidazo[1,2-a]pyridine-3-acetamide derivative of formula (IA) 
wherein Y is halogen and R3 and R4 are independently selected from hydrogen, (C1-C4)alkyl and (C2-C4)alkenyl, or R3 and R4 taken together are (C2-C3)alkylidine.
In even a further form of the invention, the compound of formula (I) is a 2-(4xe2x80x2-iodophenyl)-imidazo[1,2a]pyridine-3-acetamide derivative of formula (IA), wherein Y is at the 6-position and R3 and R4 are independently selected from hydrogen and (C1-C4)alkyl.
In one preferred method of diagnosis of the third embodiment utilising SPECT, the compound in accordance with the invention is radiolabelled with 123I.
In another preferred method of diagnosis of the third embodiment utilising PET, the compound in accordance with the invention is radiolabelled with 124I.
In one preferred method of treatment in accordance with the fifth embodiment, the compound in accordance with the invention is radiolabelled with 125I or 131I.